Reactive oxygen intermediates (ROI) play an important role in cell signaling in addition to their role in microbial killing. We have shown previously that exogenous ROI regulate activity of the
enzyme 5-lipoxygenase (5-LO) in alveolar macrophages (AM). Here, we examined the role of endogenous ROI, specifically generated by
NADPH oxidase, in the regulation of
leukotriene (LT) synthetic capacity in AM, which from
NADPH oxidase knockout (KO) mice, was significantly less than that from wild-type (WT) AM. The decrease in LT synthesis could not be explained by reduced release of the substrate for 5-LO,
arachidonic acid. However, the expression of 5-LO was reduced approximately 50% in AM from
NADPH oxidase KO mice compared with WT mice. Reduced 5-LO expression could be reproduced by treating WT AM with ROI scavengers and with selective pharmacologic inhibitors of
NADPH oxidase. Furthermore,
conditioned media from WT AM augmented 5-LO metabolism in AM from
NADPH oxidase KO mice. This decrease in 5-LO expression in
NADPH oxidase KO cells was associated with decreased expression of the
transcription factors, specificity protein-1 and early growth response-1, both of which are known to regulate 5-LO
mRNA expression. These data reveal a previously unrecognized influence of endogenous ROI generated by
NADPH oxidase on expression of the key LT
biosynthetic protein, 5-LO. In view of the antimicrobial actions of LT, a reduction in LT synthetic capacity by AM from
NADPH oxidase KO mice may contribute to the susceptibility of these animals to
infection.